PUBERTY. IT'S COMPLICATED.

As anyone who’s gone through high school (or seen Mean Girls) can attest, being a teenager is hard. Puberty is confusing and complicated—and scientists agree.What if you were a 17-year-old girl, with breasts that haven’t developed? What if you hadn’t had your first period yet? What if you were an 18-year-old boy, with a voice that hasn’t dropped, and testes that haven’t enlarged? And how do you know if you’re just a late bloomer… or have a genetic mutation?For every 1 in 10,000 children born,1 this scenario will be a reality. Hypogonadotropic hypogonadism is a condition that results in insufficient sex hormone production, and thus partial or complete failure to enter puberty. Other associated symptoms can include deafness, midfacial defects, and neurologic abnormalities—most commonly, an impaired sense of smell.2 While hypogonadism can be caused by certain drugs, systemic diseases, or brain trauma,1 the most common cause can be separated into two genetic conditions: IHH (idiopathic hypogonadotropic hypogonadism) and Kallman Syndrome.3 Patients with Kallman Syndrome (KS) have all the symptoms of IHH, as well as the additional defect in their sense of smell.

Famous for his distinctive, high contralto voice, Jimmy Scott is a jazz vocalist with Kallman Syndrome.

Far more men than women are affected by this condition,4 and for men with IHH or KS, treatment typically involves life-long testosterone replacement therapy.5 This is meant to induce pubertal development, maintain adult sex hormone levels, and improve fertility.5 In some rare cases, this treatment is enough to jumpstart testicular growth and normal hormone levels, even after coming off the therapy!5

At least for patients’ psychological wellbeing, it’s certainly best to start hormone replacement therapy as soon as possible. But it’s difficult for doctors to distinguish between late bloomers and teenagers with IHH/KS. Given that IHH/KS can be caused by mutations in any number of genes, this is a diagnosis that only becomes more obvious with time. In fact, mutations in 17 different genes have already been found, but this accounts for only 30% of IHH/KS cases!6

Most of these mutations affect genes involved in either development of the hypothalamus, or regulation of GnRH (gonadotropin-releasing hormone).2 This makes sense, given the hypothalamus’s role as a “master regulator” for normal pubertal development and reproduction:2

Puberty gets triggered when the hypothalamus begins to secrete pulses of GnRH.

This stimulates the pituitary to synthesize and secrete FSH (follicle stimulating hormone) and LH (luteinizing hormone).

These gonadotropins (FSH and LH) subsequently stimulate production of testosterone and estrogen in males and females, respectively. They also stimulate the maturation of gametes for reproduction.

This entire system, named the hypothalamic-pituitary-gonadal axis, is critical for normal puberty, and can be disrupted by any mutations that affect the secretion or action of GnRH. For instance, IHH/KS can be caused by mutations that impair the migration of GnRH-secreting neurons. Since GnRH neurons are born in the nasal placode, they must migrate from the nose to the brain, following the same trajectory as olfactory neurons. In cases of Kallman Syndrome, lack of olfactory function is presumably caused by mutations that affect the migration of both GnRH and olfactory neurons.4

Some of the most recent mutations to be identified in IHH/KS patients were found in the current #GeneOTW, WDR11. To date, six unrelated patients with hypogonadism have been found with mutations in WDR11.3 While WDR11 mutations clearly disrupt the hypothalamic-pituitary-gonadal axis, the specific function of WDR11 remains unknown. Its connection to IHH/KS could be related to its interactions with EMX1, a transcription factor that’s involved in the development of olfactory neurons.3

The identification of WDR11 as one of the genetic loci for IHH/KS will certainly aid in earlier diagnosis for some hypogonadal patients. And even though WDR11 mutations only account for 3% of IHH/KS mutations,6 every little bit helps. And if identification of a single gene just helps a handful of patients, it’s still a success if earlier diagnoses and treatments can make growing up any easier for even one IHH/KS patient! Being a teenager will always be a messy, complicated (and let’s face it, angsty) rite of passage, but while puberty might always be confusing, maybe someday its biology might not be.